‣ 3 . Specialised teams & processes 4 . Right-sized containment strategies
5 . The ability to support the entire development process Engineering controls should be the primary basis of safety ; a partner should have facilities specifically designed and built for HPAPIs . Demand for these capabilities has grown and the number of organisations attempting to capitalise on it has too . As a result , retrofitting existing facilities to accommodate HPAPI development and manufacture has become relatively common , as has the practice of relying heavily on personal protective equipment ( PPE ) as a primary basis of safety . This is not best practice , however . If the process equipment is not designed to handle HPAPIs , the containment capabilities may not align with the hazard present and thus represent a higher risk of exposure . Similarly , if the facility is not appropriately engineered to mitigate migration in case of break in containment , those potentially impacted by a breach event grows . Across the CDMO industry , many custom - often dedicated – HPAPI assets have been installed . The need for highly specialised containment can limit process applicability . Design flexibility is vital in ensuring that a CDMO can support different intermediates and steps in the development process , including diverse unit operations and a broad range of chemistries .
HPAPI processing at Sterling ’ s facility in Germantown , Wisconsin
Simply installing equipment into an isolator will certainly maintain a high level of containment , but it will impose severe constraints on the ability to make changes within that restricted space . Modifying those fixed assets will also involve significant capital cost and potentially compromise the controls . A configurable and multi-purpose design approach offers a significant advantage . This reduces additional investment and timeline requirements to handle new processes and the asset can be configured to support the process around its quality attribute control strategy . However , as with any multi-purpose facility , the risk of cross-contamination needs to be mitigated through both strong process containment and a very strong cleaning programme .
Containment options
In terms of containment , there is no ‘ one-size-fits – all ’ solution . Containment should align with the risk that exists , not just the hazard that is present . A dedicated facility , in which the isolators and process equipment are tailored for a particular unit operation , is likely to be overengineered , because not every step within the process carries the same level of risk . Having a flexible and easily configurable set-up allows the specific containment strategy to be engineered for each particular unit operation . This extends into independent evaluation of each synthetic step .
At what point in the synthesis does potency get introduced ? A conservative approach can be applied to treat all raw materials and intermediates as at least as potent as the API . This is likely to mean a higher cost as the entire process will require high-level containment equipment . This constraint can also , in turn , limit scale earlier on , when process mass intensity is higher . However , there is often no alternative , as no in vivo data associated with intermediates is generally available , as they are not targeted as potential therapeutics . The ability to predict potency and toxicity in silico is advantageous and allows a risk-based approach to be applied to containment across the entire synthetic process . Conversely , if containment is underengineered , it will fail to address the risk present . An outsourcing partner should have extensive expertise in toxicological assessments and a philosophy that focuses on creating stage-specific containment strategies . Equipment is only as good as those that operate it . The most mature partners will have a dedicated HPAPI team that has undergone thorough containment training , validated through industrial hygiene surrogate monitoring protocols . Verification of meeting these containment targets ensures that not only is the equipment performing as intended but also the operator understands how to use it . That means when the actual HPAPI is being used , there is confidence that personnel can operate safely and the processes were designed for successful execution at scale . HPAPI operations affect the entire facility . All team members , from bench chemists to maintenance and cleaning staff , should undergo extensive training on control , containment , cleaning and risk management . Highly potent compound handling is a cultural way of life for a facility ; it should include drills and protocols for incident management . Finally , the ability to manage the entire product life cycle and supply
18 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981